Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma

Sponsor
Northwestern University (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02481310
Collaborator
National Cancer Institute (NCI) (NIH), Millennium Pharmaceuticals, Inc. (Industry)
38
5
1
104.1
7.6
0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effects, good and bad of a new drug called ixazomib (also called MLN9708), when it is given along with a common treatment combination, called Dose-Adjusted EPOCH-R (DA-EPOCH-R, for short). This is a type of study called a phase I/II trial. In the phase I part, the dose of the study drug (ixazomib) will be adjusted (either up or down) to find the maximum (highest) dose that does not cause excessive (too many) harmful side effects. In the phase II part, this dose of ixazomib will be given at the maximum safe dose found in phase I. In both phase I and II, DA-EPOCH-R will be adjusted between cycles depending on how blood cell levels are affected between cycles. Ixazomib is considered investigational because it is not approved by the U.S. Food and Drug Administration (FDA). DA-EPOCH-R is a combination chemotherapy treatment developed over the last 14-15 years, and each of the drugs in this regimen is FDA-approved and considered part of the standard of care.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To evaluate the safety of ixazomib (ixazomib citrate) given with dose-adjusted etoposide, prednisone, vincristine (vincristine sulfate), cyclophosphamide, doxorubicin (doxorubicin hydrochloride), and rituximab (DA-EPOCH-R) in patients with aggressive, v-myc avian myelocytomatosis viral oncogene homolog (MYC)-aberrant lymphoid malignancies, and to determine the recommended phase II dose (RP2D) of the combination. (Phase I) II. To evaluate the efficacy, as measured by 12-month progression free survival (PFS), of ixazomib given with DA-EPOCH-R in patients with aggressive, MYC-aberrant lymphoid malignancies. (Phase II)
SECONDARY OBJECTIVES:
  1. Further evaluate the frequency and severity of toxicity. II. Further evaluate the clinical efficacy, as measured by response rate and overall survival (OS).

  2. Assess the predictive value of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scans on PFS.

TERTIARY OBJECTIVES:
  1. Determine the impact of cell of origin (COO) upon response rate, PFS, and OS.

  2. Assess the feasibility and outcomes of consolidation stem cell transplant (SCT).

OUTLINE: This is a phase I, dose-escalation study of ixazomib citrate followed by a phase II study.

INDUCTION:

Patients receive ixazomib citrate orally (PO) on day 1 and day 8 or 15; etoposide intravenously (IV), vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO twice daily (BID) on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5.

CENTRAL NERVOUS SYSTEM (CNS) PROPHYLAXIS:

Patients with a negative lumbar puncture (LP) receive methotrexate intrathecally (IT) once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly.

MAINTENANCE:

Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year (or as long as deriving benefit) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Study Design

Study Type:
Interventional
Actual Enrollment :
38 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy for Patients With MYC-aberrant Lymphoid Malignancies: The DACIPHOR Regimen
Actual Study Start Date :
Oct 28, 2015
Actual Primary Completion Date :
Sep 26, 2020
Anticipated Study Completion Date :
Jul 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (combination chemotherapy, rituximab, ixazomib)

INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity.

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
  • Drug: Cytarabine
    Given IT or intraventricularly
    Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
  • Drug: Etoposide
    Given IV
    Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
  • Drug: Ixazomib Citrate
    Given PO
    Other Names:
  • MLN-9708
  • MLN9708
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Methotrexate
    Given IT or intraventricularly
    Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039
  • Drug: Prednisone
    Given PO
    Other Names:
  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisonum
  • Prednitone
  • Promifen
  • Servisone
  • SK-Prednisone
  • Biological: Rituximab
    Given IV
    Other Names:
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
  • Drug: Therapeutic Hydrocortisone
    Given IT or intraventricularly
    Other Names:
  • Aeroseb-HC
  • Barseb HC
  • Barseb-HC
  • Cetacort
  • Cort-Dome
  • Cortef
  • Cortenema
  • Cortifan
  • Cortisol
  • Cortispray
  • Cortril
  • Dermacort
  • Domolene
  • Eldecort
  • Hautosone
  • Heb-Cort
  • HYDROCORTISONE
  • Hydrocortone
  • Hytone
  • Komed-HC
  • Nutracort
  • Proctocort
  • Rectoid
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate
  • Outcome Measures

    Primary Outcome Measures

    1. To Determine the Recommended Phase II Dose (RP2D) of Ixazomib in Combination With DA-EPOCH-R. [The first 21 days of treatment]

      The RP2D will be determined by the evaluation of dose-limiting toxicities (DLT) to find the Maximum Tolerated Dose (MTD) which will constitute the RP2D. DLTs will be defined as the occurrence of ≥ Grade 3 toxicity experienced during the first cycle (3 weeks or 21 days) of study treatment, will be determined, except for cytopenias. The dose of ixazomib will start at 2.3 mg weekly (for phase I patients) when given concurrently with DA-EPOCH-R. Single-subject cohorts (escalating in ixazomib dose) will be enrolled until the MTD is encountered, after which expansion to 3-subject cohorts will be undertaken. The MTD from phase I will equate the RP2D for ixazomib given in conjunction with DA-EPOCH-R.

    2. 12-month PFS (Progression Free Survival) of Treatment With Ixazomib in Combination With DA-EPOCH-R (Phase II) [Up to 12 months from initiation of treatment]

      12-month PFS will be defined as the percentage of patients alive and progression free 12 months from start of therapy. Patients lost to follow up will be censored from last point of contact. PFS was calculated using a Kplan-meier estimation with the probability of patients being progression free at 12 months, presented as the percentage based on this probability.

    Secondary Outcome Measures

    1. Toxicity of Treatment With Ixazomib in Combination With DA-EPOCH-R [Assessed at the beginning each cycle with up to 6 cycles of induction treatment and up to 13 cycles of maintenance treatment (1 cycle =21 days) and at approximately 21 days after the last treatment.]

      Adverse events will be assessed using CTCAE v 4.03. In general grading will be as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.

    2. Overall Survival (OS) [Up to approximately 30 months]

      OS will be defined as freedom from death by any cause and measured from time of treatment initiation and completion of follow up or death from any cause.

    3. Response Rate [After 2 cycles, then after 6 cycles and then at the discretion of the investigator for up to 13 maintenance cycles (1 cycle = 21 days)]

      Anti-tumor activity will be defined as the detection of SD (Stable Disease), Partial Response (PR), or CR (Complete Remission) by CT or PET/CT scan, and/or resolution of marrow-only involvement. CR and PR will each be assessed according to the Revised Response Criteria for Malignant Lymphoma. Assessments will be performed after cycles 2 and 6, then at the discretion of the investigator. In general: CR-Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms PR-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease should be observed. SD-fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease

    4. Assess the Predictive Value of FDG-PET/CT Scans on PFS [Up to 1 year after treatment stopped]

      Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging.

    Other Outcome Measures

    1. Determine the Impact of Cell of Origin (COO) Upon Response Rate, PFS, and OS [Up to 1 year]

      Impact of COO defined as germinal center B-cell (GCB) and non-GCB via the Hans algorithm upon response rate, PFS, and OS (applicable only to patients with DLBCL).

    2. Consolidation SCT (Stem Cell Transplant) [Up to 1 year]

      Feasibility and outcomes of consolidation SCT will be assessed. Patients will be grouped by whether consolidative SCT was performed in first remission, with PFS compared across groups (SCT vs. non-SCT).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have a histological diagnosis of any of the following (all stages allowed):

    • Diffuse large b-cell lymphoma (DLBCL) (including transformation from a previously indolent non-Hodgkin lymphoma [NHL], so long as no prior systemic treatment was given for the indolent NHL)

    • B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma

    • Burkitt lymphoma

    • MYC+ plasmablastic lymphoma by histology

    • Patients must have measurable disease (defined as >= 1.5 cm in diameter)

    • Patients must have MYC-rearrangement, as determined by fluorescent in-situ hybridization (FISH) (does not require central review)

    • The following results must be available or pending at time of registration, though results will not affect enrollment/treatment:

    • B-cell chronic lymphocytic leukemia (CLL)/lymphoma (BCL)-2 rearrangement by FISH

    • BCL-6 rearrangement by FISH NOTE: although not required, it is encouraged that MYC and BCL-2 be measured by immunohistochemistry (IHC) and clearly documented

    • Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3

    • Absolute neutrophil count (ANC) >= 1,000/mm^3

    • Platelets >= 75,000/mm^3

    • Total bilirubin =< 1.5 x upper limit of normal (ULN); NOTE: exceptions can be granted from principal investigator (PI) for instances of Gilbert's disease, and/or primarily indirect bilirubinemia, if due to recent transfusion and/or hemolysis

    • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SPGT]) =< 3 X institutional ULN

    • Calculated creatinine clearance >= 30 mL/min

    • NOTE: platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before registration; these requirements do not apply to those with marrow involvement of lymphoma (any extent)

    • Female patients must meet one of the following criteria:

    • Postmenopausal for at least 1 year prior to registration

    • Surgically sterile

    • Of childbearing potential and agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug

    • Of childbearing potential and agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject NOTE: periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

    • Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug

    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject NOTE: periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

    • Females of child-bearing potential (FOCBP) must have a negative pregnancy test within

    days prior to registration on study

    • Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study
    Exclusion Criteria:
    • Patients who have had more than one cycle of prior chemoimmunotherapy for diagnosis of NHL are not eligible; NOTE: such patients must have fully recovered (ie, =< grade 1 toxicity) from the reversible effects of prior chemotherapy before starting treatment on the current protocol

    • Patients who have had major surgery within 4 weeks prior to registration are not eligible

    • Patients who have had radiotherapy within 14 days before registration are not eligible; NOTE: If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib

    • Patients who have an infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment are not eligible

    • Patients who have evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months are not eligible

    • Patients who have undergone systemic treatment, within 14 days prior to registration, with strong inhibitors of cytochrome P450 superfamily (CYP)1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort are not eligible

    • Patients who have a clinically active hepatitis B or C virus infection are not eligible; NOTE: those with evidence of exposure to hepatitis B virus (HBV) may enroll so long as HBV viral load is negative AND subject is willing/able to take appropriate antiviral prophylaxis to prevent reactivation

    • Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol are not eligible

    • Patients who have a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible

    • Patients who have a known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing are not eligible

    • Patients who have been diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease are not eligible; NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection

    • Patients who have >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period are not eligible

    • Patients who are participating in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of registration and throughout the duration of this trial are not eligible

    • Female patients who are nursing or have a positive pregnancy test during screening are not eligible

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Northwestern University Chicago Illinois United States 60611
    2 Tufts University Medford Massachusetts United States 02155
    3 Rutgers Cancer Institute of New Jersey New Brunswick New Jersey United States 08901
    4 Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland Ohio United States 44195
    5 Medical College of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Northwestern University
    • National Cancer Institute (NCI)
    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Principal Investigator: Barbara Pro, MD, Northwestern University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Northwestern University
    ClinicalTrials.gov Identifier:
    NCT02481310
    Other Study ID Numbers:
    • NU 14H09
    • NCI-2015-00400
    • X16042
    • STU00200596
    • NU 14H09
    • P30CA060553
    First Posted:
    Jun 25, 2015
    Last Update Posted:
    Feb 21, 2022
    Last Verified:
    Feb 1, 2022

    Study Results

    Participant Flow

    Recruitment Details The study opened to accrual on Aug 24, 2015 with the first patient being enrolled and starting treatment on 10.28.2015. The study closed to any further accrual on October 1sts 2019 with 38 patients enrolled on study. The study closed prior to reaching full accrual goal of up to 55 patients.
    Pre-assignment Detail First patient was enrolled to Cohort 1. Second patient enrolled to Cohort 2. Third patient enrolled to Cohort 3. Forth and fifth patient enrolled to Cohort 2. All further patients enrolled to phase II (same dose as Cohort 2).
    Arm/Group Title Treatment- Cohort 1(Combination Chemotherapy, Rituximab, Ixazomib 2.3 mg) Treatment Cohort 2 and Phase II (Combination Chemotherapy, Rituximab, Ixazomib 3 mg) Treatment - Cohort 3 (Combination Chemotherapy, Rituximab, Ixazomib 4 mg)
    Arm/Group Description INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
    Period Title: Induction Treatment (6 Cycles)
    STARTED 1 36 1
    Reached First Evaluable Response 1 34 1
    Complete 6 Cycles 1 30 1
    COMPLETED 1 30 1
    NOT COMPLETED 0 6 0
    Period Title: Induction Treatment (6 Cycles)
    STARTED 1 21 1
    Started Maintenance Treatment 1 21 1
    COMPLETED 1 21 1
    NOT COMPLETED 0 0 0
    Period Title: Induction Treatment (6 Cycles)
    STARTED 1 32 1
    COMPLETED 1 29 1
    NOT COMPLETED 0 3 0

    Baseline Characteristics

    Arm/Group Title Treatment- Cohort 1(Combination Chemotherapy, Rituximab, Ixazomib 2.3 mg) Treatment Cohort 2 and Phase II (Combination Chemotherapy, Rituximab, Ixazomib 3 mg) Treatment - Cohort 3 (Combination Chemotherapy, Rituximab, Ixazomib 4 mg) Total
    Arm/Group Description INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV Total of all reporting groups
    Overall Participants 1 36 1 38
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    0
    0%
    25
    69.4%
    0
    0%
    25
    65.8%
    >=65 years
    1
    100%
    11
    30.6%
    1
    100%
    13
    34.2%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    11
    30.6%
    0
    0%
    11
    28.9%
    Male
    1
    100%
    25
    69.4%
    1
    100%
    27
    71.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    1
    2.8%
    0
    0%
    1
    2.6%
    Not Hispanic or Latino
    1
    100%
    35
    97.2%
    1
    100%
    37
    97.4%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    3
    8.3%
    0
    0%
    3
    7.9%
    White
    1
    100%
    33
    91.7%
    1
    100%
    35
    92.1%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title To Determine the Recommended Phase II Dose (RP2D) of Ixazomib in Combination With DA-EPOCH-R.
    Description The RP2D will be determined by the evaluation of dose-limiting toxicities (DLT) to find the Maximum Tolerated Dose (MTD) which will constitute the RP2D. DLTs will be defined as the occurrence of ≥ Grade 3 toxicity experienced during the first cycle (3 weeks or 21 days) of study treatment, will be determined, except for cytopenias. The dose of ixazomib will start at 2.3 mg weekly (for phase I patients) when given concurrently with DA-EPOCH-R. Single-subject cohorts (escalating in ixazomib dose) will be enrolled until the MTD is encountered, after which expansion to 3-subject cohorts will be undertaken. The MTD from phase I will equate the RP2D for ixazomib given in conjunction with DA-EPOCH-R.
    Time Frame The first 21 days of treatment

    Outcome Measure Data

    Analysis Population Description
    1 patient enrolled at 2.3 mg of ixazomib, 3 patients enrolled at 3 mg of ixazomib, 1 patient enrolled at 4 mg ixazomib in phase I were evaluable for this endpoint.
    Arm/Group Title Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Arm/Group Description INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
    Measure Participants 5
    Number [mg]
    3
    2. Primary Outcome
    Title 12-month PFS (Progression Free Survival) of Treatment With Ixazomib in Combination With DA-EPOCH-R (Phase II)
    Description 12-month PFS will be defined as the percentage of patients alive and progression free 12 months from start of therapy. Patients lost to follow up will be censored from last point of contact. PFS was calculated using a Kplan-meier estimation with the probability of patients being progression free at 12 months, presented as the percentage based on this probability.
    Time Frame Up to 12 months from initiation of treatment

    Outcome Measure Data

    Analysis Population Description
    Only patients included in the phase II dose are included in this endpoint per protocol.
    Arm/Group Title Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Arm/Group Description INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
    Measure Participants 36
    Number (95% Confidence Interval) [probability (%) of patients alive]
    75.84
    3. Secondary Outcome
    Title Toxicity of Treatment With Ixazomib in Combination With DA-EPOCH-R
    Description Adverse events will be assessed using CTCAE v 4.03. In general grading will be as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.
    Time Frame Assessed at the beginning each cycle with up to 6 cycles of induction treatment and up to 13 cycles of maintenance treatment (1 cycle =21 days) and at approximately 21 days after the last treatment.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    Title Overall Survival (OS)
    Description OS will be defined as freedom from death by any cause and measured from time of treatment initiation and completion of follow up or death from any cause.
    Time Frame Up to approximately 30 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    Title Response Rate
    Description Anti-tumor activity will be defined as the detection of SD (Stable Disease), Partial Response (PR), or CR (Complete Remission) by CT or PET/CT scan, and/or resolution of marrow-only involvement. CR and PR will each be assessed according to the Revised Response Criteria for Malignant Lymphoma. Assessments will be performed after cycles 2 and 6, then at the discretion of the investigator. In general: CR-Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms PR-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease should be observed. SD-fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease
    Time Frame After 2 cycles, then after 6 cycles and then at the discretion of the investigator for up to 13 maintenance cycles (1 cycle = 21 days)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    Title Assess the Predictive Value of FDG-PET/CT Scans on PFS
    Description Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging.
    Time Frame Up to 1 year after treatment stopped

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Other Pre-specified Outcome
    Title Determine the Impact of Cell of Origin (COO) Upon Response Rate, PFS, and OS
    Description Impact of COO defined as germinal center B-cell (GCB) and non-GCB via the Hans algorithm upon response rate, PFS, and OS (applicable only to patients with DLBCL).
    Time Frame Up to 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    Title Consolidation SCT (Stem Cell Transplant)
    Description Feasibility and outcomes of consolidation SCT will be assessed. Patients will be grouped by whether consolidative SCT was performed in first remission, with PFS compared across groups (SCT vs. non-SCT).
    Time Frame Up to 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment
    Adverse Event Reporting Description Secondary endpoints are written to have phase I & II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
    Arm/Group Title Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Arm/Group Description INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
    All Cause Mortality
    Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Affected / at Risk (%) # Events
    Total 6/38 (15.8%)
    Serious Adverse Events
    Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Affected / at Risk (%) # Events
    Total 20/38 (52.6%)
    Blood and lymphatic system disorders
    Febrile Neutropenia 7/38 (18.4%) 8
    Febrile neutropenia 1/38 (2.6%) 1
    Cardiac disorders
    Cardiac Arrest 1/38 (2.6%) 1
    Gastrointestinal disorders
    Esophageal perforation 1/38 (2.6%) 1
    Small intestine and colonic perforation 1/38 (2.6%) 1
    Infections and infestations
    Cholecystitis 1/38 (2.6%) 1
    Lung infection 1/38 (2.6%) 1
    duodenitis 1/38 (2.6%) 1
    Sepsis 1/38 (2.6%) 1
    parainfluenza 3 1/38 (2.6%) 1
    Urinary tract infection 1/38 (2.6%) 1
    Lung infection 1/38 (2.6%) 1
    Sepsis 1/38 (2.6%) 1
    Injury, poisoning and procedural complications
    Spinal fracture (lumbar) 1/38 (2.6%) 1
    Metabolism and nutrition disorders
    Hyponatremia 1/38 (2.6%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    gastric adenocarcinoma 1/38 (2.6%) 1
    Renal and urinary disorders
    Acute kidney injury 1/38 (2.6%) 1
    Acute kidney injury 1/38 (2.6%) 1
    Respiratory, thoracic and mediastinal disorders
    COPD Exacerbation 1/38 (2.6%) 1
    Respiratory failure 1/38 (2.6%) 1
    Respiratory failure 1/38 (2.6%) 1
    Vascular disorders
    Thromboembolic event 1/38 (2.6%) 1
    Thromboembolic event - pulmonary embolism 1/38 (2.6%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Combination Chemotherapy, Rituximab, Ixazomib)
    Affected / at Risk (%) # Events
    Total 38/38 (100%)
    Blood and lymphatic system disorders
    Anemia 38/38 (100%)
    Blood and lymphatic system disorders - Other, specify 3/38 (7.9%)
    Febrile neutropenia 3/38 (7.9%)
    Lymph node pain 3/38 (7.9%)
    Leukocytosis 2/38 (5.3%)
    Cardiac disorders
    Sinus tachycardia 12/38 (31.6%)
    Cardiac disorders - Other, specify 9/38 (23.7%)
    Palpitations 2/38 (5.3%)
    Atrial fibrillation 1/38 (2.6%)
    Chest pain - cardiac 1/38 (2.6%)
    Left ventricular systolic dysfunction 1/38 (2.6%)
    Sinus bradycardia 1/38 (2.6%)
    Ear and labyrinth disorders
    Tinnitus 4/38 (10.5%)
    Ear and labyrinth disorders - Other, specify 3/38 (7.9%)
    Ear pain 1/38 (2.6%)
    Endocrine disorders
    Hypothyroidism 3/38 (7.9%)
    Endocrine disorders - Other, specify 1/38 (2.6%)
    Eye disorders
    Blurred vision 5/38 (13.2%)
    Eye disorders - Other, specify 5/38 (13.2%)
    Cataract 3/38 (7.9%)
    Retinal detachment 2/38 (5.3%)
    Watering eyes 2/38 (5.3%)
    Eye pain 1/38 (2.6%)
    Vitreous hemorrhage 1/38 (2.6%)
    Gastrointestinal disorders
    Constipation 32/38 (84.2%)
    Nausea 29/38 (76.3%)
    Mucositis oral 22/38 (57.9%)
    Diarrhea 19/38 (50%)
    Vomiting 16/38 (42.1%)
    Abdominal pain 14/38 (36.8%)
    Gastrointestinal disorders - Other, specify 8/38 (21.1%)
    Hemorrhoids 7/38 (18.4%)
    Dry mouth 6/38 (15.8%)
    Abdominal distension 5/38 (13.2%)
    Dyspepsia 4/38 (10.5%)
    Dysphagia 4/38 (10.5%)
    Gastroesophageal reflux disease 4/38 (10.5%)
    Bloating 3/38 (7.9%)
    Flatulence 3/38 (7.9%)
    Oral pain 3/38 (7.9%)
    Toothache 2/38 (5.3%)
    Anal hemorrhage 1/38 (2.6%)
    Fecal incontinence 1/38 (2.6%)
    Lower gastrointestinal hemorrhage 1/38 (2.6%)
    Upper gastrointestinal hemorrhage 1/38 (2.6%)
    General disorders
    Fatigue 35/38 (92.1%)
    Edema limbs 20/38 (52.6%)
    Pain 15/38 (39.5%)
    Chills 10/38 (26.3%)
    Fever 9/38 (23.7%)
    General disorders and administration site conditions - Other, specify 9/38 (23.7%)
    Localized edema 8/38 (21.1%)
    Infusion related reaction 5/38 (13.2%)
    Non-cardiac chest pain 4/38 (10.5%)
    Flu like symptoms 2/38 (5.3%)
    Gait disturbance 2/38 (5.3%)
    Malaise 2/38 (5.3%)
    Edema face 1/38 (2.6%)
    Facial pain 1/38 (2.6%)
    Infusion site extravasation 1/38 (2.6%)
    Hepatobiliary disorders
    Cholecystitis 1/38 (2.6%)
    Hepatobiliary disorders - Other, specify 1/38 (2.6%)
    Immune system disorders
    Immune system disorders - Other, specify 2/38 (5.3%)
    Infections and infestations
    Infections and infestations - Other, specify 7/38 (18.4%)
    Urinary tract infection 4/38 (10.5%)
    Sepsis 3/38 (7.9%)
    Upper respiratory infection 3/38 (7.9%)
    Lung infection 2/38 (5.3%)
    Sinusitis 2/38 (5.3%)
    Enterocolitis infectious 1/38 (2.6%)
    Esophageal infection 1/38 (2.6%)
    Skin infection 1/38 (2.6%)
    Wound infection 1/38 (2.6%)
    Injury, poisoning and procedural complications
    Bruising 7/38 (18.4%)
    Fall 1/38 (2.6%)
    Injury, poisoning and procedural complications - Other, specify 1/38 (2.6%)
    Vascular access complication 1/38 (2.6%)
    Investigations
    Lymphocyte count decreased 38/38 (100%)
    Platelet count decreased 38/38 (100%)
    White blood cell decreased 34/38 (89.5%)
    Neutrophil count decreased 33/38 (86.8%)
    Alkaline phosphatase increased 24/38 (63.2%)
    Alanine aminotransferase increased 22/38 (57.9%)
    Weight loss 22/38 (57.9%)
    Aspartate aminotransferase increased 21/38 (55.3%)
    Investigations - Other, specify 13/38 (34.2%)
    Creatinine increased 12/38 (31.6%)
    Blood bilirubin increased 8/38 (21.1%)
    Weight gain 4/38 (10.5%)
    INR increased 3/38 (7.9%)
    Cholesterol high 2/38 (5.3%)
    Lymphocyte count increased 1/38 (2.6%)
    Urine output decreased 1/38 (2.6%)
    Metabolism and nutrition disorders
    Hypoalbuminemia 37/38 (97.4%)
    Hypocalcemia 34/38 (89.5%)
    Hypokalemia 33/38 (86.8%)
    Hyperglycemia 24/38 (63.2%)
    Hypophosphatemia 24/38 (63.2%)
    Hyponatremia 20/38 (52.6%)
    Anorexia 13/38 (34.2%)
    Hypernatremia 10/38 (26.3%)
    Hypomagnesemia 10/38 (26.3%)
    Hyperkalemia 8/38 (21.1%)
    Hypoglycemia 7/38 (18.4%)
    Metabolism and nutrition disorders - Other, specify 7/38 (18.4%)
    Hypercalcemia 6/38 (15.8%)
    Hyperuricemia 6/38 (15.8%)
    Dehydration 4/38 (10.5%)
    Obesity 4/38 (10.5%)
    Hypermagnesemia 2/38 (5.3%)
    Acidosis 1/38 (2.6%)
    Alkalosis 1/38 (2.6%)
    Tumor lysis syndrome 1/38 (2.6%)
    Musculoskeletal and connective tissue disorders
    Back pain 16/38 (42.1%)
    Bone pain 10/38 (26.3%)
    Generalized muscle weakness 10/38 (26.3%)
    Pain in extremity 9/38 (23.7%)
    Musculoskeletal and connective tissue disorder - Other, specify 7/38 (18.4%)
    Myalgia 6/38 (15.8%)
    Neck pain 4/38 (10.5%)
    Muscle weakness lower limb 3/38 (7.9%)
    Arthralgia 2/38 (5.3%)
    Chest wall pain 2/38 (5.3%)
    Arthritis 1/38 (2.6%)
    Musculoskeletal deformity 1/38 (2.6%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 2/38 (5.3%)
    Nervous system disorders
    Peripheral sensory neuropathy 30/38 (78.9%)
    Headache 20/38 (52.6%)
    Dysgeusia 15/38 (39.5%)
    Dizziness 14/38 (36.8%)
    Paresthesia 8/38 (21.1%)
    Peripheral motor neuropathy 4/38 (10.5%)
    Tremor 4/38 (10.5%)
    Lethargy 3/38 (7.9%)
    Aphonia 1/38 (2.6%)
    Cerebrospinal fluid leakage 1/38 (2.6%)
    Dysesthesia 1/38 (2.6%)
    Dysphasia 1/38 (2.6%)
    Encephalopathy 1/38 (2.6%)
    Hypersomnia 1/38 (2.6%)
    Memory impairment 1/38 (2.6%)
    Nervous system disorders - Other, specify 1/38 (2.6%)
    Presyncope 1/38 (2.6%)
    Sinus pain 1/38 (2.6%)
    Vasovagal reaction 1/38 (2.6%)
    Pregnancy, puerperium and perinatal conditions
    Pregnancy, puerperium and perinatal conditions - Other, specify 1/38 (2.6%)
    Psychiatric disorders
    Anxiety 16/38 (42.1%)
    Insomnia 14/38 (36.8%)
    Depression 12/38 (31.6%)
    Confusion 2/38 (5.3%)
    Psychiatric disorders - Other, specify 2/38 (5.3%)
    Delirium 1/38 (2.6%)
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify 9/38 (23.7%)
    Urinary frequency 8/38 (21.1%)
    Urinary incontinence 3/38 (7.9%)
    Acute kidney injury 2/38 (5.3%)
    Hematuria 2/38 (5.3%)
    Urinary retention 2/38 (5.3%)
    Reproductive system and breast disorders
    Reproductive system and breast disorders - Other, specify 4/38 (10.5%)
    Breast pain 1/38 (2.6%)
    Erectile dysfunction 1/38 (2.6%)
    Respiratory, thoracic and mediastinal disorders
    Cough 20/38 (52.6%)
    Dyspnea 18/38 (47.4%)
    Nasal congestion 15/38 (39.5%)
    Respiratory, thoracic and mediastinal disorders - Other, specify 14/38 (36.8%)
    Sore throat 9/38 (23.7%)
    Postnasal drip 5/38 (13.2%)
    Sleep apnea 5/38 (13.2%)
    Epistaxis 4/38 (10.5%)
    Hoarseness 4/38 (10.5%)
    Productive cough 4/38 (10.5%)
    Allergic rhinitis 3/38 (7.9%)
    Atelectasis 3/38 (7.9%)
    Pleural effusion 3/38 (7.9%)
    Respiratory failure 2/38 (5.3%)
    Hiccups 1/38 (2.6%)
    Hypoxia 1/38 (2.6%)
    Pulmonary edema 1/38 (2.6%)
    Pulmonary hypertension 1/38 (2.6%)
    Sneezing 1/38 (2.6%)
    Wheezing 1/38 (2.6%)
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders - Other, specify 11/38 (28.9%)
    Alopecia 7/38 (18.4%)
    Dry skin 5/38 (13.2%)
    Rash maculo-papular 5/38 (13.2%)
    Hyperhidrosis 3/38 (7.9%)
    Nail loss 3/38 (7.9%)
    Pruritus 3/38 (7.9%)
    Skin ulceration 3/38 (7.9%)
    Bullous dermatitis 2/38 (5.3%)
    Pain of skin 2/38 (5.3%)
    Rash acneiform 2/38 (5.3%)
    Erythema multiforme 1/38 (2.6%)
    Nail discoloration 1/38 (2.6%)
    Vascular disorders
    Hypertension 34/38 (89.5%)
    Thromboembolic event 5/38 (13.2%)
    Hypotension 4/38 (10.5%)
    Hot flashes 3/38 (7.9%)
    Hematoma 1/38 (2.6%)
    Lymphedema 1/38 (2.6%)
    Vascular disorders - Other, specify 1/38 (2.6%)

    Limitations/Caveats

    The study closed accrual prior to the planned sample size being enrolled and treated on the study.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Barbara Pro, MD
    Organization Northwestern University
    Phone 312-695-6832
    Email barbara.pro@northwestern.edu
    Responsible Party:
    Northwestern University
    ClinicalTrials.gov Identifier:
    NCT02481310
    Other Study ID Numbers:
    • NU 14H09
    • NCI-2015-00400
    • X16042
    • STU00200596
    • NU 14H09
    • P30CA060553
    First Posted:
    Jun 25, 2015
    Last Update Posted:
    Feb 21, 2022
    Last Verified:
    Feb 1, 2022